Pink Pepto-bismol(copyright) liquid, which has bismuth subsalicylate as its active ingredient, is popular among consumers for quick relief of heartburn, indigestion, upset stomach, diarrhea, and nausea. Some consumers, though, do not like the taste or feel of such a liquid in their mouths, nor do they wish to chew a tablet with a similar taste, A swallowable tablet would be ideal for those consumers, but it is technically difficult to formulate and make a swallowable, bismuth-containing tablet which will give quick relief To be valued by consumers, such a tablet must break up quickly in the stomach so that the active ingredient is absorbed into the blood rapidly enough to provide quick relief. An especially preferred, swallowable, bismuth-containing solid dose form is one which provides relief from symptoms in about the same amount of time as liquid Pepto-bismol(copyright) takes to provide relief.
U.S. Pat. No. 5,225,197, Bolt et al, issued Jul. 6, 1993, describes a chewable tablet which includes a medicament in a chewable base such as mannitol and an effervescent couple such as citric acid-sodium bicarbonate.
U.S. Pat. No. 5,096,714, Kuhrts, issued Mar. 17, 1992 describes a prolonged dosage composition consisting essentially of a gel-forming dietary fiber, a biologically absorbable drug or other therapeutic agent, and certain disintegrants, namely, a physiologically acceptable edible acid and a mineral salt which release a physiologically acceptable gas upon ingestion.
The present invention relates to swallowable solid dose form compositions for treating upper gastrointestinal tract distress, comprising, by weight of the composition:
(a) from about 2% to about 25% of carbonate or bicarbonate salt;
(b) from about 0.5% to about 15% of disintegrating agent;
(c) from about 5% to about 70% of bismuth subsalicylate;
(d) from about 0.1% to about 3% of anionic or nonionic surfactant; and
(e) from about 15% to about 50% of microcrystalline cellulose.
The present invention further relates to a method for treating heartburn, indigestion, upset stomach, diarrhea, and/or nausea in humans or other mammals, the method comprising administering to a human or other mammal in need of such treatment a safe and effective amount of a pharmaceutical composition according to the present invention.
The swallowable, solid dose form compositions herein are comprised of (bi)carbonate salt, disintegrating agent, bismuth subsalicylate, anionic or nonionic surfactant, and microcrystalline cellulose, which are each described below. The present compositions preferably further comprise mannitol, silica, polyvinyl pyrrolidone, and other ingredients, which are also described below. The percentages given below are by weight of the composition unless otherwise indicated.
The swallowable (i.e. not chewable) solid dose form compositions herein preferably do not comprise a gel-forming dietary fiber such as psyllium, or an effervescent couple such as citric acid-sodium bicarbonate, or a physiologically acceptable edible acid and a mineral salt which release a physiologically acceptable gas upon ingestion. The present compositions are not prolonged dosage compositions; instead they are designed for quick dissolution in the stomach and absorption into the bloodstream. It is not necessary to include calcium chloride in the present compositions.
The compositions herein comprise from about 2% to about 25%, preferably from about 5% to about 20%, most preferably from about 8% to about 15%, by weight of the composition, of carbonate and/or bicarbonate salt. Preferred are calcium, sodium, potassium, and/or magnesium salts of carbonate (most preferred) and/or bicarbonate. Most preferred is calcium carbonate. Without meaning to be bound by theory, it is believed that the calcium carbonate at this level is acting as a processing aid and is not included to impart effervescence to this swallowable solid dose form.
The compositions herein comprise from about 0.5% to about 30%, preferably from about 1% to about 20%, most preferably from about 2% to about 10%, by weight of the composition, of disintegrating agent.
The disintegrating agent is preferably selected from the group consisting of sodium starch glycolate, cross-linked polyvinyl pyrrolidone, croscarmellose sodium (a cross-linked cellulose), polyacrilin potassium (an ion exchange resin), alginic acid, starch, and mixtures thereof. The disintegrating agent is more preferably sodium starch glycolate or cross-linked polyvinyl pyrrolidone (available as Crospovidone), and is most preferably sodium starch glycolate (available as Explotab(copyright) from Edward Mendell Co.)
The compositions herein comprise from about 5% to about 70%, preferably from about 10% to about 60%, most preferably from about 30% to about 50%, by weight of the composition, of bismuth subsalicylate. The average particle size of the bismuth subsalicylate (before incorporation with the remaining ingredients into the final form) is preferably from about 1 to about 50, more preferably from about 2 to about 30, most preferably from about 3 to about 10, microns. Without meaning to be bound by theory, this small particle size is believed to contribute to the efficacy of the solid dose forms herein by facilitating dissolution of the solid dose form in the stomach and allowing quicker absorption into the blood. Relief of symptoms is thus experienced rapidly, most preferably in an amount of time comparable to liquid Pepto-bismol(copyright).
The compositions herein comprise from about 0.1% to about 3%, preferably from about 0.2 to about 1%, most preferably from about 0.4 to about 0.6%, by weight of the composition, of anionic and/or nonionic surfactant. Any anionic and nonionic surfactants, including synthetics, suitable for use in a swallowable solid dose form may be used in the present compositions.
Nonionic surfactants for use herein include compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound, which may be aliphatic or alkyl aromatic in nature. The surfactant is preferably a nonionic surfactant and is preferably selected from the group consisting of polyethylene oxide condensates of alkyl phenols; products derived from the condensation of ethylene oxide with the product resulting form the reaction of propylene oxide and ethylene diamine products; the condensation product of aliphatic alcohols having from 8 to 18 carbon atoms with ethylene oxide; long chain tertiary amine oxides corresponding to the following general formula wherein R1 contains an alkyl, alkenyl, or monohydroxy alkyl radical of from about 8 to about 18 carbon atoms, from 0 to about 10 ethylene oxide moieties, and from 0 to 1 glyceryl moiety, and R2 and R3 contain from 1 to about 3 carbon atoms and from 0 to about 1 hydroxy group; long chain tertiary phosphine oxides; and long chain dialkyl sulfoxides containing one short chain alkyl or hydroxy alkyl radical of from 1 to about 3 carbon atoms and one long hydrophobic chain which contain alkyl, alkenyl, hydroxy alkyl, or keto alkyl radicals containing from about 8 to about 20 carbon atoms, from 0 to about 10 ethylene oxide moieties, and from 0 to 1 glyceryl moiety; and mixtures thereof
The most preferred surfactant for use herein is polyoxyethylene sorbitan monooleate.
Anionic surfactants for use herein include the alkali metal salts of organic sulfuric reaction products having in their molecular structure an alkyl radical containing from 8-22 carbon atoms and a sulfonic acid or sulfuric acid ester radical.
If the surfactant is an anionic surfactant, it is preferably selected from the group consisting of: the sodium, ammonium, potassium or triethanolamine alkyl sulfates, sodium coconut oil fatty acid monoglyceride sulfates and sulfonates, sodium or potassium salts of sulfuric acid esters of the reaction product of 1 mole of a higher fatty alcohol and 1 to 12 moles of ethylene oxide, sodium or potassium salts of alkyl pheno ethylene oxide per molecule and in which the alkyl radicals contain from 8 to 12 carbon atoms, sodium alkyl glyceryl ether sulfonates, the reaction products of fatty acids having from 10 to 22 carbon atoms esterified with isethionic acid and neutralized with sodium hydroxide, water soluble salts of condensation products of fatty acids with sarcosine, and mixtures thereof.
The compositions herein further comprise from about 15% to about 50%, preferably from about 20% to about 40%, most preferably from about 25% to about 35%, by weight of the composition, of microcrystalline cellulose. Preferred is Avicel (copyright) PH102 microcrystalline cellulose NF from FMC Corp. (Philadelphia, Pa.). Preferably, the average particle size of the microcrystalline cellulose is from about 20 to about 200 microns, most preferably from about 80 to about 120 microns.
The compositions herein preferably further comprise, by weight of the composition:
(a) from about 2% to about 25%, preferably from about 5% to about 20%, most preferably from about 8% to about 15%, of soluble sugars and/or sugar alcohols, most preferably mannitol;
(b) from about 0.02% to about 0.5%, preferably from about 0.05% to about 0.2%, most preferably from about 0.08% to about 0.15%, of silica, most preferably Cab-o-Sil(copyright) from Cabot Corp.;
(c) from about 0.1% to about 5%, preferably from about 0.5% to about 2%, most preferably from about 0.6% to about 1.5%, of magnesium stearate; and
(d) from about 0.5% to about 10%, preferably from about 1% to about 5%, most preferably from about 1.5% to about 3%, of polyvinyl pyrrolidone, most preferably Povidone(copyright).
The soluble sugars are preferably selected from the group consisting of dextrose, sucrose, glucose, xylose, ribose, mannose, galactose, fructose, maltose, and mixtures thereof, and the sugar alcohols are preferably selected from the group consisting of xylitol, mannitol, sorbitol, and mixtures thereof Most preferred is mannitol.
Conventional ingredients of swallowable, solid dose forms, such as dye, may also be included herein.
A preferred composition herein comprises, by weight of the composition:
(a) from about 8% to about 15% of calcium carbonate;
(b) from about 2% to about 10% of sodium starch glycolate;
(c) from about 3% to about 50% of bismuth subsalicylate;
(d) from about 0.4% to about 0.6% of anionic or nonionic surfactant; and
(e) from about 25% to about 35% of microcrystalline cellulose.
It preferably further comprises, by weight of the composition:
(a) from about 5% to about 20% of mannitol;
(b) from about 0.05% to about 0.2% of silica;
(c) from about 0.1% to about 5% of magnesium stearate; and
(d) from about 1% to about 5% of polyvinyl pyrrolidone.
The present invention further relates to a method for treating heartburn, indigestion, upset stomach, diarrhea, and/or nausea in humans or other mammals, the method comprising administering to a human or other mammal in need of such treatment a safe and effective amount of a pharmaceutical composition according to the present invention.
The composition herein is preferably in the form of a tablet or capsule, more preferably in the form of a tablet shaped like a capsule. Conventional tablet/capsule making procedures are employed. Tablet hardness should be low enough to provide integrity and stability, but not so high as to interfere with dissolution of the tablet in the stomach.
The composition herein is preferably orally self-administered by humans and is preferably used for treating the same symptoms that liquid Pepto-bismol(copyright) is used to treat. The tablets/capsules are preferably taken by mouth to relieve heartburn, indigestion, upset stomach, diarrhea, and/or nausea in humans or other mammals. A composition herein is preferably orally administered for treatment of acid indigestion, heartburn or sour stomach.
Preferably, two caplets of about 675 milligrams per caplet (which includes approximately 262 milligrams of bismuth subsalicylate per caplet) are taken with water every xc2xd to 1 hour as needed up to a maximum of 8 doses in a 24 hour period (adult dose). The recommended dose for children 9-12 years of age is one caplet, for children 6-9 years of age is ⅔ caplet, for children 3-6 years of age is ⅓ caplet. Children under 3 should see a physician.